Drug Interactions between aspirin / caffeine / dihydrocodeine and viloxazine

MONITOR: Coadministration with potent CYP450 1A2 inhibitors such as fluvoxamine may increase the plasma concentrations of caffeine in a dose-dependent manner. Caffeine is primarily metabolized by CYP450 1A2 and is considered a probe substrate for the isoenzyme. In 12 healthy volunteers, pretreatment with fluvoxamine for 7 days (10 mg once or twice a day) resulted in a 2-fold increase in the mean 24-hour area under the plasma concentration-time curve (AUC) of a single 100 mg oral dose of caffeine. When the dosage of fluvoxamine was increased (25 mg once or twice a day for 7 days), the mean 24-hour AUC of single-dose caffeine increased 5-fold. The peak plasma concentration (Cmax) of caffeine increased 40% and 141%, respectively, during these treatment phases. Another study found that fluvoxamine (50 mg daily for 4 days, then 100 mg daily for 8 days) decreased the median total clearance of a single 200 mg oral dose of caffeine by 80% and increased the half-life from 5 to 31 hours in eight healthy volunteers.

MANAGEMENT: Caution is advised if caffeine is administered concurrently with potent CYP450 1A2 inhibitors. Dosage adjustment should be considered in patients who experience excessive adverse effects of caffeine such as nausea, vomiting, headache, nervousness, irritability, agitation, restlessness, insomnia, tinnitus, tremors, and tachycardia.

MONITOR: Coadministration with viloxazine may increase the plasma concentrations of drugs that are substrates of CYP450 3A4 and/or CYP450 2D6 leading to increased toxicity. The proposed mechanism is decreased clearance due to viloxazine-mediated inhibition of CYP450 3A4 and/or CYP450 2D6. The product labeling describes viloxazine as a weak inhibitor of CYP450 3A4 and CYP450 2D6.

MANAGEMENT: Caution is advised if viloxazine is used concomitantly with drugs that are substrates of CYP450 3A4 and/or CYP450 2D6, particularly those with a narrow therapeutic range. Monitor for adverse reactions of the CYP450 3A4 or CYP450 2D6 substrate and adjust dosages as needed.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.